Core Clinical Biochemistry Flashcards

Question 1

Q

What is the difference between endocrine, paracrine and autocrine secretion?

Answer

A

ENDOCRINE gland hormone secretion directly into blood- act systemically
PARACRINE system secretes hormones- act locally (on tissues in same organ)
AUTOCRINE secretion affects the cell secreting the protein

Question 2

Q

Where is the Pituitary Gland located?

Answer

A

In the Sella Turcica beneath hypothalamus

* Weighs 500-1000mg

Question 3

Q

What are the different parts of the Pituitary Gland?

Answer

A

• Anterior & posterior parts
o 75% ant lobe (also called adenohypophysis)- outpouching of oral cavity (Rathke’s pouch)
o 25% post lobe- downgrowth of hypothalamus

Question 4

Q

What are the Causes of Anterior Pituitary Hypofunction?

Answer

A

Tumours (non-secretory adenoma, metastatic carcinoma)- e.g. destroys pituitary gland, or is benign non-secretory
Trauma
Infarction
Inflammation (granulomatous, autoimm, other infecs)
Iatrogenic

Question 5

Q

What are Primary Pituitary Tumours? What can they cause? What are common types?

Answer

A

Can cause hypOfunction
Majority are ADENOMAS & BENIGN;
Can be from any hormone producing cell
If functional clinical effect 2ndry to hormone being produced e.g. ACTH will cause cushings
Local effects due to pressure on optic chiasma/ adjacent pituitary

o Prolactinoma- COMMONEST, galactorrhoea & menstrual disturbance
o Growth hormone secreting- gigantism in children, acromegaly in adults
o ACTH secreting (stim adrenal cortex)- Cushings syndrome

Question 6

Q

What is Prolactinoma?

Answer

A

COMMONEST anterior pituitary adenoma;

Symptoms include: galactorrhoea & menstrual disturbance

Question 7

Q

Where is the Thyroid Gland?

Answer

A

Bilobed, joined by isthmus encased in thin fibrous capsule
Located level of 5th, 6th & 7th vertebrae in anterior neck (close to trachea- 2nd & 3rd tracheal rings)
Weight 18g (adult males), 15g (adult females)

Question 8

Q

What does the Thyroid Gland touch and have a common boundary with?

Answer

A

o Larynx thyroid cartilage

o Recurrent laryngeal nerve (in trachea-oesophageal groove near posterior aspects of lateral lobes)

Question 9

Q

What is the development and migration of the Thyroid Gland ?

Answer

A

Main part migrates from foregut to ant neck (remnant is foramen caecum at junction ant 2/3 & post 1/3 of tongue)- forms follicular cells
Ultimobrachial body forms in brachial arches & fuses with main bit laterally- gives rise to C cells (can form medullary carcinomas)

Question 10

Q

What is Lingual thyroid?

Answer

A

Lingual thyroid (type of ectopic thyroid)- small nodule of ectopic thyroid tissue on dorsal tongue (posterior to circumvallate papillae) – failure to migrate from foramen caecum to neck
> 75% of patients with lingual thyroid have no other thyroid tissue. 70% hypothyroid; 10% with cretinism (stunted physical & mental growth from congenital thyroid hormone deficiency)

Question 11

Q

What is Ectopia & Heterotropia of the Thyroid Gland ?

Answer

A

Foramen cecum to suprasternal notch.
Lingual thyroid: Most common, usually at base of tongue.
Lingual thyroid (type of ectopic thyroid)- small nodule of ectopic thyroid tissue on dorsal tongue (posterior to circumvallate papillae) – failure to migrate from foramen caecum to neck
> 75% of patients with lingual thyroid have no other thyroid tissue. 70% hypothyroid; 10% with cretinism (stunted physical & mental growth from congenital thyroid hormone deficiency)
Other sites: Sella turcica, larynx, trachea, aortic arch, esophagus, heart, pericardium, liver, GB, pancreas, vagina.

Question 12

Q

What is Chronic Lymphocytic Thyroiditis?

Answer

A

HASHIMOTOS - HYPOTHYROIDISM

• Autoimmune chronic inflammatory disorder associated with diffuse enlargement & thyroid autoantibodies.

Question 13

Q

What is the epidemiology of Chronic Lymphocytic Thyroiditis?

Answer

A

Much more common in females than males.

* Peak age 59 years.

Question 14

Q

What are the clinical features of Chronic Lymphocytic Thyroiditis?

Answer

A

Diffusely enlarged non-tender gland.
Serum thyroid antibodies elevated.
Lymphocytic infiltration of thyroid parenchyma, often with germinal centre formation.
Many patients become hypothyroid.

Question 15

Q

What can Chronic Lymphocytic Thyroiditis also cause?

Answer

A

80-fold increased risk of thyroid lymphoma.
Increased risk of papillary carcinoma of the thyroid.
Common cause of hypothyroidism

Question 16

Q

What is Graves Disease?

Answer

A

Autoimmune process results in clinical hypothyroidism (after Grave’s treatment) & diffuse hyperplasia of follicular epithelium.
One of common cause of hypErthyroidism

Question 17

Q

What is the epidemiology of Graves Disease?

Answer

A

Incidence 1% world wide.
Responsible for 80% of cases of hyperthyroidism.
Much more common in females than men.
Peak in third and fourth decades.

Question 18

Q

What are the clinical features of Graves Disease?

Answer

A

Symptoms of hyperthyroidism.
Physical findings – Pretibial myxoedema (fluid collection in deeper layers of skin), hair loss, wide-eyed stare or proptosis, tachycardia, hyperactive reflexes.
Thyroid diffusely enlarged.
T3 and T4 elevated. TSH markedly suppressed.
Thyroid autoantibodies, especially thyroid stimulating immunoglobulin (bind to TSH recep & cause T3 & T4 release)

Question 19

Q

What can Graves Disease also cause?

Answer

A

One of common cause of hypErthyroidism

• May develop permanent hypothyroidism?

Question 20

Q

What is a Multinodular Goitre?

Answer

A

Enlargement of thyroid with varying degrees of nodularity.
1 or more thyroid nodules discovered by patient or health care provider.
Most patients are euthyroid (normally functioning thyroid gland- hormone levels normal).
Dominant nodule may be mistaken clinically for thyroid carcinoma.
Tracheal compression or dysphagia may develop with large nodules.

Question 21

Q

What is a Follicular Adenoma?

Answer

A

Benign encapsulated tumour with evidence of follicular cell differentiation.
Females more than males.
Wide age range, usually fifth to sixth decade.
Painless neck mass, often present for years.
Solitary nodule involving only one lobe (unlike multinodular goitre).
Usually cold nodule on radioactive iodine imaging

Question 22

Q

What are examples of Malignant Tumours of the Thyroid?

Answer

A

1.1% of new cancers
0.32% of cancer deaths
85% are differentiated thyroid carcinoma
5-9% are medullary carcinoma (from C cells- associated with MAN)
1-2% are anaplastic carcinoma (most aggressive- only live 6-9 mnths from time of diagnosis, if poorly differentiated then live slightly longer)
1-3% are malignant lymphoma

Question 23

Q

What is a Papillary Carcinoma?

Answer

A

Commonest type of thyroid carcinoma >70%

* Familial, autosomal dominant non-medullary thyroid carcinoma

Question 24

Q

What is the epidemiology of Papillary Carcinoma?

Answer

A

Female predominance 2.5:1

* Wide age range mean 43 years

Question 25

Q

What is the aetiology of Papillary Carcinoma?

Answer

A

FAP (familial adenomas polyposis)
Cowden’s syndrome
Therapeutic irradiation
Radiation exposure
Activation of RET or NTRK1
Variety of chromosomal translocations or inversions

Question 26

Q

What are the genetics of Papillary Carcinoma?

Answer

A

Variety of chromosomal translocations or inversions
Fusion of RET tyrosine kinase regions with constitutively expressed thyroid proteins eg PTC1 in inv(10)(q11;q21). PTC2 t(10;17(q11.2;q21)
BRAF V600E mutation
RAS mutations

Question 27

Q

What is the Macroscopic appearance of Papillary Carcinoma?

Answer

A

•	Macroscopic appearance;
o	Ill defined, infiltrative
o	Some encapsulated (better prognosis) 
o	May be cystic
o	Granular

Question 28

Q

What condition are Psammoma bodies seen in? What are they?

Answer

A

Papillary Carcinoma

calcified rings usually seen in papillary carcinoma can (seen in USS)

Question 29

Q

What are Follicular Neoplasms? What mutation is present? What are the types?

Answer

A

All show RAS mutations

Follicular adenoma
Minimally invasive follicular carcinoma
Widely invasive follicular carcinoma
Hurthle cell neoplasms

Question 30

Q

What is a Follicular Carcinoma?

Answer

A

10-20% of all thyroid cancers
90% present with solitary nodule in thyroid (helps with diagnosis)
10% present with distant metastasis

Question 31

Q

What are the different types of Follicular Carcinoma?

Answer

A

Minimally invasive < 5% metastasis

* Widely invasive >60% metastasis

Question 32

Q

What is Minimally invasive Follicular Carcinoma?

Answer

A

• Minimally invasive < 5% metastasis
• Minimally invasive ;
o Completely encapsulated.
o Invasion only detectable histologically

Question 33

Q

What is a Widely invasive Follicular Carcinoma?

Answer

A

•	Widely invasive >60% metastasis
•	Widely invasive;
o	Macroscopic evidence of invasion. 
o	Widespread invasion histologically. 
o	Minimally invasive but tumour invades > 4 capsular blood vessels

Question 34

Q

What is Hurthle Cell (Oncotic) Carcinoma?

Answer

A

Recognised large acidophilic cells in canine thyroid
Cells with oncoyctic cytoplasm
These were parafollicular or C cells
3% of all differentiated thyroid carcinomas
Median age 53 ( range 24-85 years)
Sex ratio of F:M; 7:3

Question 35

Q

What are the clinical features of Hurthle Cell (Oncotic) Carcinoma?

Answer

A

• Clinical behaviour;
o Unlike Follicular Carcinoma there is a significant incidence of cervical lymph node metastases
o Can be multifocal
o Common haematogenous sites – Bone, Liver and Lung

Question 36

Q

What is Primary hyperparathyroidism?

Answer

A

excessive section of parathyroid hormone from one or more glands (PHPT)

Question 37

Q

What is the incidence of Primary Hyperparathyroidism ?

Answer

A

25-28 cases per 100,000 population

* White women over 60 – 190/100,000

Question 38

Q

What is pathogenesis Primary Hyperparathyroidism ?

Answer

A

Aging, tumorigenesis in general
Association with ionizing irradiation
MEN 2a syndrome- multiple endocrine neoplasia

Question 39

Q

What are the different symptoms of Primary Hyperparathyroidism ?

Answer

A

ASYMPTOMATIC OR OLIGOSYMPTOMATIC: 50+%
ARTERIAL HYPERTENSION : 5-48%
PSYCHIATRIC PROBLEMS: 14-20%
HYPERCALCEMIA SYMPTOMS: 20%
DECREASED RENAL FUNCTION :4-14%
OSTEOPOROSIS :12%
HYPERPARATHYROID BONE DISEASE: 8%
HYPERCALCEMIA SYMPTOMS: 8%
UROLITHIASIS: 4-7%

Question 40

Q

What are the different types of Primary Hyperparathyroidism ?

Answer

A

SINGLE ADENOMA (most common) 85 - 90%
DIFFUSE CHIEF OR CLEAR CELL HYPERPLASIA 10 – 15%
CARCINOMA 1%

Question 41

Q

What is Parathyroid Adenoma?

Answer

A

An encapsulated benign neoplasm of parathyroid cells.
1 per thousand people.
Symptoms of hypercalcaemia.
Association with MEN1 and MEN2 syndrome and hyperparathyroidism and jaw tumour syndrome.
Single enlarged parathyroid gland; remaining glands suppressed and small.
HRPT2 gene mutation- parathyroid carcinoma

Question 42

Q

What is Secondary Hyperparathyroidism ?

Answer

A

hyperplasia of glands with elevated PTH in response to hypocalcemia
o Seen in patients with renal insufficiency, malabsorption, vitamin D deficiency

• Non-neoplastic increase in parathyroid parenchymal cell mass within all parathyroid tissue with a known stimulus.
• Common in patients with renal failure and on dialysis.
• Identical pathologic features to primary hyperplasia. May be associated with massive gland enlargement
• PTH levels fall when affected gland removed
above same as tertiary

Question 43

Q

What is Tertiary Hyperparathyroidism ?

Answer

A

adenoma in association with longstanding secondary hyperparathyroidism

Question 44

Q

What is Parathyroid Carcinoma ?

Answer

A

Malignant tumour from parathyroid parenchymal cells.
Only 1% of primary hyper-parathyroidism.
Symptoms referable to excess calcium
Indolent with recurrences common (about 50%).
50% 10-year survival.
Treated with surgery.

Question 45

Q

What are the layers of the Adrenal glands?

Answer

A

Adrenal glands on top of kidneys
Diff layers;
• Central part- medulla
• Outer part- cortex (has 3 layers- glonerulosa(aldosterone), fasciculata(cortisol), reticularis (catecholamines))
Diff hormones from diff layers- so depending on where affected affects type of tumour
e.g. Zona fasiculata- Cushing’s syndrome

Question 46

Q

What is Cushing’s Syndrome?

Answer

A

• Collection of signs and symptoms due to prolonged exposure to cortisol.

Question 47

Q

What are the causes of Cushing’s Syndrome?

Answer

A

Exogenous causes - excessive glucocorticoid medication

* Endogenous causes - adrenal cortical tumours, adrenal cortical hyperplasia and ACTH secreting pituitary adenoma

Question 48

Q

What are the signs and symptoms of Cushing’s Syndrome

Answer

A

Signs and symptoms - high BP, moon face (oedema of face), central obesity, buffalo hump, weak muscles, weak bone, excess sweating, mood swings, headaches, excess sweating, osteoporosis, chronic fatigue. Women may have increased hair growth (hirsuitism) and irregular menstruation.
Insomnia

Question 49

Q

What is Paraneoplastic Cushing’s ?

Answer

A

• Paraneoplastic Cushing’s seen in small cell lung carcinoma- tumour not affecting renal/ pituitary

Question 50

Q

What is Conn’s Syndrome ?

Answer

A

Hyperaldosteronism, primary 7 secondary, W>M, 30-50yrs
Excess aldosterone production by adrenal cortex leading to low renin levels (controlled by renin-angiotensin system)
Aetiology include adrenal cortical hyperplasia, adenoma and familial hyperaldosteronism

Question 51

Q

What are the signs and symptoms of Conn’s Syndrome?

Answer

A

high BP, headache, muscular weakness, muscle spasms, excessive urination.

Question 52

Q

What is Addison’s Disease ?

Answer

A

Primary adrenal cortical insufficiency caused by adrenal dysgenesis (lack of formation of adrenal gland), adrenal destruction, autoimmune adrenalitis, TB
Secondary to failure of ACTH secretion
5.3 per million population.
High mortality if not diagnosed.
Autoimmune form is most common.
Treatment with long term steroid replacement
If undiagnosed can prove fatal

Question 53

Q

What are the signs and symptoms of Addison’s Disease?

Answer

A

• Triad of hyperpigmentation, postural hypotension and hyponatraemia.

Question 54

Q

What is a Adrenal Cortical Nodule?

Answer

A

Benign non-functional nodules of adrenal cortex.
Between 1.5 and 3% of population. Higher in elderly, hypotensive and diabetic patients.
No clinical symptoms (as non functional). Incidental discovery on radiographic studies.
No treatment required.

Question 55

Q

What is a Adrenal Cortical Adenoma?

Answer

A

Benign neoplastic proliferation of adrenal cortical tissue.
Incidence from 1-5% of population.
Symptoms related to endocrine hyperfunction (hypertension, Cushing’s symptoms and virilisation)- depending on which layer of adrenal cortex affected depends on which hormone affected
Aldosterone-producing tumours cause Conn’s syndrome. Cortisol-producing tumours cause Cushing’s syndrome. Rare tumours cause virilisation.

Question 56

Q

What is a Adrenal Cortical Carcinoma?

Answer

A

Malignant counterpart of adrenal cortical adenoma.
3% of endocrine neoplasms. About 1 per million of population.
Symptoms related to hormone excess.
Abdominal mass.
Prognosis, age and stage dependent (e.g. if has metastasised or not).
5 year survival about 70%.

Question 57

Q

What is a Phaeochromocytoma?

Answer

A

Catecholamine-secreting tumour arising from adrenal medulla.
Extra renal- paragandioma
8 per million of population.
10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial and 10% in children.
Most are sporadic but familial syndromes MEN2a and 2b, von Recklinghausen’s disease and von Hippel-Lindau disease
symptoms of hypertension, palpitations, headaches, anxiety.
Elevated urine catecholamines, adrenaline, noradrenaline.
Excellent prognosis when benign and properly managed surgically.
Malignant tumour may pursue an aggressive course

Question 58

Q

What are the three different Types of Hormones?

Answer

A

Peptide hormones (e.g. PTH, ACTH, TSH)
Steroid hormones (e.g. Testosterone, Oestradiol, Cortisol)
Tyrosine-based hormones e.g. Thyroxine (T4) and Triiodothyronine (T3)

Question 59

Q

What inhibits GnRH?

Answer

A

inhibited by estradiol/inhibin/progesterone and stimulated by environment an higher brain centres
Inhibin inhibits FSH production via negative signalling

Question 60

Q

What inhibits GHRH?

Answer

A

inhibited by somatostatin

Question 61

Q

What inhibits PRH?

Answer

A

inhibited by dopamine

Question 62

Q

What are the tree models of steroid hormone response?

Answer

A

Classical model= steroid hormone dissociates from plasma carrier protein & diffuses across cell memb. Enters cell & binds to intracell recep & alters gene transcription
Receptor-mediated endocytosis= steroid hormone bound to plasma protein carrier brought into cell via cell-surface recep. Complex broken inside lysosome & free steroid hormone diffuses into cell & acts on genomic level/ undergoes metabolism
Signalling through cell surface receps= free steroid hormone alters intracell signalling by binding to cell-surface receps. Steroid hormone could directly exert these effects or alter signalling by blocking actions of peptide hormones , alteration of intracellular signalling including ion channels and PLs
• Steroid hormones- circulate bound to serum proteins
• Steroid hormones made when there is a stimulus to make them & they act rapidly

Question 63

Q

What is the Classical model of steroid hormone function?

Answer

A

steroid hormone dissociates from plasma carrier protein & diffuses across cell memb. Enters cell & binds to intracell recep & alters gene transcription

Question 64

Q

What is the Receptor-mediated endocytosis model of steroid hormone function?

Answer

A

steroid hormone bound to plasma protein carrier brought into cell via cell-surface recep. Complex broken inside lysosome & free steroid hormone diffuses into cell & acts on genomic level/ undergoes metabolism

Answer 65

A

free steroid hormone alters intracell signalling by binding to cell-surface receps. Steroid hormone could directly exert these effects or alter signalling by blocking actions of peptide hormones , alteration of intracellular signalling including ion channels and PLs
• Steroid hormones- circulate bound to serum proteins
• Steroid hormones made when there is a stimulus to make them & they act rapidly

Answer 66

A

Peptide Hormone Signalling Cascades
• Cascade amplifies signal e.g. insulin action depends on calcium entering cell
• C-peptide-initiated signaling cascades; regulating diff signaling cascades e.g. phospholipase C (PLC) & NF-κB pathway.
• These intracellular signaling events are likely mediated by a G protein-coupled recep e.g. GPR146
• GPR146 interacts with G protein (Gαi or Gαo)
• GPR146 may interact physically with additional proteins on the cell memb e.g. an integrin
• C-peptide and insulin appear to functionally interact, particularly at the level of Akt.

Answer 67

A

stimulates T cell production

Answer 68

A

activates GLUT-1 transporter

Answer 69

A

o Stimulation for hypO-function
o Suppression for hypErfunction

When to take blood samples- physiological & pathological factors
When to use integrated urine sampling
Free, bound & total hormone concs

Answer 70

A

Normal pituitary & thyroid
Primary thyroid disease (in primary synthetic hromone for that hormone( - not enough thyroid hormones produced
Secondary thyroid disease – i.e pituitary tumour

Answer 71

A

Stress stimulation from amygdala to paraventicular nucleus which releases CTRH (corticotropin releasing hormone) this causes ACTH release which acts on adrenal cortex to cause cortisol release. CRF also controls the stress response- brain and peripheral function
Cortisol causes stress response
Glucocorticoids then causes –ve feedback to ensure stress response doesn’t carry on by sending -ve signals to all areas of the brain.

Answer 72

A

Which is primary cortisol excess?- Disease in Adrenal

* Which is secondary cortisol excess?- Due to excess ACTH

Answer 73

A

in pituitary disease, May get adrenal gland hypertrophy
Adrenal makes lots of cortisol-ve feedback on pituitary
Ectopic- something outside of normal tissue secreting hormone when it shouldn’t , Get effects of cortisol excess

Answer 74

A

o	Benign carcinoid tumors of the lung
o	Small cell tumours of the lung
o	Islet cell tumours of the pancreas
o	Medullary carcinoma of the thyroid
o	Tumours of the thymus gland

Answer 75

A

Primary adrenal insufficiency- disease in adrenal gland so doesn’t make cortisol- so can’t respond to stresses (EMERGENCY SITUATION), lots of ACTH secreted to try to get cortisol produc, no –ve feedback so excess ACTH
Secondary adrenal insufficiency due to pituitary prob (not enough ACTH secreted)
Exogenous cortisol- ACTH not secreted because of exogenous cortisol
Measure cortisol after cortisol being given e.g. dexamethasone, may detect cortisol in their circ but person won’t be able to mount a stress response (EMERGENCY)

Answer 76

A

Diurnal rhythm in cortisol secretion
E.g. won’t be secreting cortisol at night
Peak produc at 9am when wake up (above 150nmols/L)
Peaks after eating & exercise
So taking cortisol values during the day not informative for diagnosis of insufficiency or excess also random day test isn’t useful

Answer 77

A

Cushing’s DISEASE- tumour producing ACTH
Cushings SYNDROME- anything producing secondary excess

• Conduct dexamethasone suppression test

Answer 78

A

o	Obesity; moon face, central, shoulders 
o	Skin; thin, purple striae, bruising 
o	Hypertension 
o	Glucose intolerance 
o	Menstrual disturbances/ impotance 
o	Thin limbs/ muscle weakness 
o	Back pain due to osteoporosis 
o	Psychiatric disturbances; depression psychosis

Answer 79

A

• In ability to make enough cortisol in response to stress
• Due to adrenal atrophy/ destruction
• Serum cortisol after 250 mmol Synacthen 350 nmol/L (no increase in cortisol- shows adrenal insufficiecncy)
Syncathen test; syncathen given IM, measure serum cortisol at 9am (baseline), if unsufficeincy this is low but could be higher, syncathin (ACTH stim)- meaure later & expect to see an increment & if no incrememnt then insufficiency

Answer 80

A

o	Tiredness
o	Weight loss
o	Pigmentation
o	Hypoglycaemia
o	Abdominal pain
o	Hypovolaemic collapse

Answer 81

A

TSH ↑ & thyroxine ↓ -unresponsive thyroid
TSH ↑ & thyroxine ↑ -npituitary gland overproduction or feedback failure
TSH ↓ & thyroxine ↓- pituitary failure
TSH ↓ & thyroxine ↑- thyroid gland overproduction

Answer 82

A

TRH from hypothalamus stimulates pituitary to release TSH which stimulates the thyroid to release T3 and T4.
T3 and T$ inhibit the pituitary and the hypothalamus and the pituitary also releases TSH which inhibits the hypothalamus.

Answer 83

A

Thyroid hormones in critically unwell patients (‘sick euthyroid disease’)
• Euthyroid (normally functioning thyroid)- no thyroid disease
• If very unwell (shock, MI etc)- cytokines mount inflammatory response, then act centrally on thalamus & systemically
• Cytokines inhibit iodide uptake in thyroid & thyroid peroxidase activity & deiodinase= decrease T4 and T3synthesis and secretion and also decreased TRH secretion from the hypothalamus due to the central effects of cytokines

Answer 84

A

• FSH & LH values change through the cycle
• Ovaries failing (may be menopausal)- no eistrodial –ve feedback occurring
But if still menstruating may have just taken sample mid cycle where there is a peak of FSh & LH- so taking blood sample to measure hormones not always accurate (need to also look at the clinical pic- also help you to decide WHEN to take the sample to help interpret results)

Answer 85

A

Peak in foetus & infancy (spotty at around 2 months- as surge in testosterone)
Low conc in childhood until puberty
In adulthood- peaks & trophs throughout the day
Andropause- degree of testicular failure & testosterone decreases

Answer 86

A

Integration of fluctuating single serum hormone e.g. pulsatile secretion e.g. 24hr urine sample & measure cortisol from this
Integration of multiple hormones
Analysis of unstable serum hormones but more stable in urine
Collection at time of symptoms (when symptomatic can take a spot urine)
Avoid venepuncture
e.g. Phaeochromocytoma (tumour of adrenal medulla NOT cortex), chromaffin cells release excess catcholamines e.g. adrenaline (get palpitations, hypertenion, flushing-red flag for phaeochromocytoma)- mesure catecholamine metabolites (as catcholamines themselves unsatble so measure products they are metabolised to in urine- DO 24hr URINE is suspect phaeochromocytoma)
e.g. metanephrine & normetanephrine in a 24hr urine collection

Answer 87

A

Insulinomas- rare pancreatic endocrine tumors
Most insulinomas are solitary & benign, but when in patients with MEN1 multiple tumors are usually present
Nonspecific symptoms (e.g. hypoglycaemic symptoms- e.g. shivering, feeling nervous/ faint) & small size of these tumors- difficulties of diagnosis & localization
Hypoglycemia & endogenous hyperinsulinemia are diagnostic
Can remove insulinoma by enucleation
Before operation- transabdominal USS (localise tumour) or CT (identify potentially malig or metastatic tumours)
Intraoperative ultrasound- so far best localization of insulinoma, improving success rate and possibly decreasing the already low postoperative complication rate for resection of these tumors.
Excision of benign insulinomas- long-term cure.

Answer 88

A

• Hormones in equilibrium: Free + protein-bound = total hormone (equilibrium)
• fT4 and fT3 are the biologically active forms of thyroid hormones (pmol/L)
• fT4 and fT3 in the circulation are bound to proteins (TBG, albumin)- NOT biologically active when bound to protein
• Immunoassays – use labelled Ab to recognise and bind fT3 / fT4;
o Take sample & add fluorescent antibodies to it
o The antibodies will capture the free hormones (then you can wash sample out & measure the fluorescent antibodies bound to homones to see how much free hormones are in sample)
o BUT results may be affected as need to add excess antibodies to sample so when you leave the reaction to happen the antibodies may take hormones that are bound to the proteons in the sample- so not just measuring the free but also some of the bound hormone- so may look like you have raised level of free hormones when don’t
o Immunoassays specific to hormones- antibodies labelled, capture & measure labelled to give idea of how much free sample in hormone
o BUT hormones in equalib- e.g. if capture hormone might cause mass effect causing bound hormone to be released
o So need to be careful when assay so don’t affect the equalib

Answer 89

A

Annual cycles- hair growth
Monthly cycles- menses
Diurnal (daily)- cortisol
Rapid amplitude cycles- insulin
Stress related- ant. pituitary hormones
Stimulus related- insulin

Answer 90

A

• People use glucose for fuel
• 3 sources of glucose in the body;
o Dietary carbs
o Glycogenolysis
o Gluconeogenesis (glucose produc from other precursor molecules)
• Glucose is stored as glycogen in liver & muscle
• In fasting- glycogen broken down= glucose

Answer 91

A

• Maintained at about 5mmol/l
• Achieved by balancing liver glucose release, dietary intake & use of glucose by the body to keep glucose at a stable level e.g. use more in exercise
• Insulin (made by pancreas)- controls glucose release from liver & promotes glucose UPTAKE in tissues
Hypoglycaemia <4mmol/L
Hyperglycaemia >11mmol/L

Answer 92

A

• Made by beta cells in Islets of Langerhans in pancreas
• Secreted in response to raised blood glucose conc
• Reduces blood glucose through diff mechanisms
Effects of insulin;
• Glucose- lowering effects;
o Increases cellular glucose UPTAKE
o Increases SYNTHESIS of GLYCOGEN
o Inhibits gluconeogenesis
o Inhibits glycogenolysis
• Other metabolic effects;
o Increases fatty acid, triglyceride & protein synthesis
o Inhibits ketogenesis, lipolysis & proteolysis (so if not enough insulin- build up of ketones)

Answer 93

A

Hormones that INCREASE blood glucose;
•	Glucagon
•	Adrenaline (made by adrenal gland) &amp; growth hormone (made by ant pituitary);
o	Stimulate glycogenolysis 
o	Stimulate lipolysis  
•	Cortisol (made by adrenal gland)
o	Stimulates gluconeogenesis 
o	Increases glycogen synthesis 
o	Stimulates proteolysis 
o	Reduces tissue glucose use

Answer 94

A

• Made by alpha cells of pancreatic islets
• Rise in blood glucose decreases it’s secretion
• Increases blood glucose by;
o Stimulating glycogenolysis
o Stimulating gluconeogenesis
• Also increases ketogenesis & lipolysis

Answer 95

A

Diabetes- medical condition with high blood glucose levels
• Blood glucose level drifts up- chronic hyperglycaemia
• Is a syndrome of raised blood glucose (hyperglycaemia) due to diff causes
• Has acute & chronic complications
• Patients often have high BP & high lipid levels
• How common;
o Leeds: 30,000 in 730,000 pop (4%)
o Prevalence rising fast
o Associated with rise in obesity & reduction in physical activity
o High prevalence in Asians & Afro-Caribbeans

Answer 96

A

Syndrome- collection of symptoms & signs that may be due to more than 1 cause (more than 1 cause of high blood glucose in diabetes)
Symptoms: thirst, polyuria, weight loss, tiredness
Signs: dry mouth, weight loss, glycosuria, hyperglycaemia
Diabetes may be due to several causes

Answer 97

A

Insulin deficiency (body doesn’t make enough) or resistance to it’s action or both
Causes increased gluconeogenesis & glycogenolysis (so more glucose from liver to blood) & impaired glucose uptake by cells (so blood glucose keeps rising)
Leads to chronic hyperglycaemia

Answer 98

A

Diabetes Diagnosis (excluding gestational diabetes)
• Typical symptoms and 1 of;
o Random plasma glucose (taken at any time of day) ≥11.1 mmol/L or
o Fasting plasma glucose (e.g. overnight fast) ≥7.0 mmol/L or
o 2 hr post-load plasma glucose ≥11.1 mmol/L during 75g oral glucose tolerance test (OGTT) (measure before & after 2hrs) or
o HbA1c ≥48 mmol/mol (6.5%) (long term marker)
• If no typical diabetes symptoms, repeat testing on a diff day to confirm diagnosis (so have 2 values above cut off)

Answer 99

A

• Can be oral (OGTT) or IV (IVGTT)
• OGTT;
o Fasting plasma glucose
o Then 75g oral glucose load (e.g. sugary drink)
o Plasma glucose at intervals & as 2hrs post-glucose load
o Interpretation;
 Fasting: normal <6.1mmol/l, diabetic ≥ 7mmol/l
 2-hr post-glucose load: normal <7.8mmol/L, diabetic ≥ 11.1 mmol/l

Answer 100

A

In between normal & diabetic range
Impaired fasting glucose: plasma glucose ≥ 6.1 mmol//L and <7mmol/l
Impaired glucose tolerance: 2 hour post-glucose load plasma glucose ≥7.8 and <11.1 mmol/l, on the 75g OGTT
HbA1c 42-47 mmol/mol (high risk of going onto type 2 diabetes)

Answer 101

A

• HbA1c;
o Glycated Hb- depends on blood glucose level
o As RBCs live for 120 days, this values shows you blood glucose for a couple of months (rather than just 1 moment in time)
o Not reliable in patient’s with anaemia
o A test for diabetes diagnosis & assessing degree of glycaemic control
• Renal function
• Liver function (might have fatty liver causing affected LFTs)
• Lipids
• Thyroid function (as thyroid disease also autoimm)

Answer 102

A

• Diagnosed using 75g 2-hour OGTT
• Gestational Diabetes diagnosed if:
o Fasting plasma glucose ≥ 5.6 mmol/L
o 2-hour post-glucose load plasma glucose ≥ 7.8 mmol/L

Answer 103

A

Type 1: insulin dependent
LADA (Latent Autoimmune Diabetes in Adults)
Type 2
Gestational Diabetes
Pancreatic disorders
Drug induced
Endocrine disorders
Ethnic variants of diabetes
Genetic syndromes

Answer 104

A

Autoimmune destruction of the insulin producing islet beta cells so can’t make insulin
Insulin deficient: insulin dependent (exogenous insulin injections otherwise can get diabetic ketoacidosis)
Usually young, but can be ANY age
Symptoms; thirst, passing lots of urine etc over a couple of months (other types of diabetes develop more slowly)
Autoantibody tests: ICA, IA2, GAD
Often other endocrine disorders in patient or family

Answer 105

A

Subtype of type 1 diabetes
Older patients, often female
Medical or family history of related autoimmune conditions: type 1 diabetes, thyroid, PA, Addison’s (autoimm- don’t make enough steroids), coeliac, vitiligo
Presents often as ‘type 2’ diabetes- present slowly
Progressive deterioration in control, increasing therapy (need insulin treatment)
Autoantibodies: GAD, ICA, tTG, TPO

Answer 106

A

Insulin resistant/deficient (don’t respond to insulin the way normal people do)- overtime less made by pancreas
Not absolutely insulin dependent
Strong family history
Often obese or overweight (metabolic syndrome associated with this)
Usually hypertensive and hyperlipidaemic
Initailly lifestyle changes e.g. control blood glucose

Answer 107

A

Often obese, ethnic minority
Ketosis when physically stressed with intercurrent illness e.g. infecs (may need insulin treatment for these periods of time when unwell)
Temporarily requires insulin
Not insulin dependent

Answer 108

A

Diabetes & obesity are closely interlinked
Not every diabetic person is overweight
Not every overweight person is diabetic or will become diabetic
Population association between overweight and diabetes

Answer 109

A

Diabetes arising/ diagnosed in pregnancy
In late 2nd or early 3rd trimester
Diabetes appears during pregnancy & resolves after pregnancy (associated with insulin resistance)
At risk of diabetes in later pregnancy
At risk of diabetes in future- as have underlying insulin resistance that preg brings to the surface

Answer 110

A

(Secondary diabetes- diabetes caused by anything that’s not type 1 or 3 diabetes)
Chronic or acute pancreatitis
Need insulin treatment
Calcific, tropical pancreatitis- calcium deposits damage insulin producing cells
Pancreatectomy (e.g. if had pancreatic cancer)
Pancreatic cancer- as damage beta cells
Cystic fibrosis- blocked ducts in pancreas causing inflamm & destroying beta cells (acute illness can also cause resistance)
Haemochromatosis- hereditary iron overload storage disorder (iron deposits in tissues e.g. pancreas- damages cells)

Answer 111

A

Thiazide) diuretics
• Steroids e.g. for rheumatoid arthritis or asthma
• Antipsychotics e.g. Olansazpine
• Psychiatric drugs: weight gain

Answer 112

A

(adrenal gland tumour- causes adrenal medulla to make too much adrenaline & noradrenaline)- adrenaline is a counter- regulatory hormone so too much adrenaline=too much glucose in blood

Answer 113

A

‘Jamaican’ diabetes, Afro-Caribbeans;
o Mimics type 2 diabetes
o Ketosis prone
o Not particularly obese
o On and off insulin therapy for episodes of high glucose (associated with acute illness)
o Variable insulin requirements as when recover from illness sometimes don’t need inulin anymore just manage with e.g. diet
o But always at risk of having episodes in the future if they become unwell
o Also called Flatbush diabetes

Answer 114

A

US Afro-Americans

Answer 115

A

tropical diabetes

Answer 116

A

secondary diabetes

Answer 117

A

(associated with pancreatitis)

Answer 118

A

Most people are diabetic on Pacific Island of Nauru- highest prevalence of diabetes in the world (genetic predisposition & lifestyle factors)
Pima native Americans of Arizona- Pima tribe: obesity & diabetes (highest prevalence of diabetes in the world)
Friedreich’s ataxia (neurodegen condition)
Dystrophia myotonica
Maturity Onset Diabetes of the Young (MODY)

Answer 119

A

‘Mason-type’ diabetes;
o Subtype of type 2 diabetes- clinical features of type 2 but present under age 25
o Autosomal dominant pattern
o 1-2% of diabetic cases
o Onset under 25
o Insulin not required initially
o 6 diff types- have mutations in genes; Glucokinase, HNF 1A, HNF 4A

Answer 120

A

• Divalent cation – Ca2+ (beware EDTA!!)
• EDTA binds divalent cations (e.g. calcium) so stops clotting process
• Physiologically important
o Muscle contraction
o Neuronal excitation
o Enzyme activity (Na/K ATPase, hexokinase etc.)
o Blood clotting
• Structurally important- key component of hydroxyapatite Ca₁₀(PO₄)₆(OH)₂ (predominant mineral in bone)

Answer 121

A

• Monovalent anion (-vly chrged so will bind +vly chrged entities)– PO4
• Physiological importance
o The P in ATP – our fuel!
o Intracellular signalling
o Cellular metabolic processes e.g. glycolysis
• Structural importance
o Backbone of DNA
o Component of hydroxyapatite Ca₁₀(PO₄)₆(OH)₂
o Membrane phospholipids
• PREDOMINANTLY INTRACELLULAR

Answer 122

A

•	Divalent cation – Mg2+ 
•	Physiological importance
o	Cofactor for ATP– our fuel!
o	Neuromuscular excitability (memb potentials) 
o	Enzymatic function
o	Regulates ion channels
•	Structural importance- comprises 0.5 – 1% of bone matrix
•	PREDOMINANTLY INTRACELLULAR

Answer 123

A

If have normal renal function- not physically possible to have a extremely high K+
EDTA is a K+ salt

Answer 124

A

• Calcium normally tightly regulated 2.20 -2.60 mmol/L
• Two key controlling factors:
o PTH (parathyroid hormone)
o Vitamin D and metabolites
• Vit D helps with Ca intake, PTH helps balance
• Complex (but well-characterised) relations between
o GI uptake (where get calcium from)
o Renal Clearance
o Bone

Answer 125

A

Total Ca = Ionised Ca + Bound Ca + Complexed Ca
• Ionised Calcium
o Physiologically active fraction- biologically active
o Calcium sensing receptor- controls regulations that control ca homeostasis
o Cellular Effects
o Regulation of PTH
• Bound Calcium
o Physiologically inactive
o Albumin main binding protein (~50%) (can also bind to immunoglobulins so if have myeloma will affect calcium)
• Complexed Calcium
o Salts – calcium phosphate & calcium citrate (if too much will create salts in high concs)

Answer 126

A

•	Calcium values can be corrected for changes in albumin
•	Adjusted Ca = Total Ca + (40 - Alb) x 0.025
•	Reference range is unchanged but patient samples are adjusted for better diagnostic performance
o	Total Ca (not all biologically active)	 2.20 - 2.60 mmol/L
o	 Ca(adj) 	2.20 - 2.60 mmol/L

Answer 127

A

H+ & Ca2+ compete for binding to –ve albumin
Too many hydroxyl & less H+ so more Ca binds to albumin 1.25, less ionized 1.0
e.g. normal adj Ca but if acidotic than that is not normal calcium- look at everything together .
Acidosis reduces Ca-albumin, Alkalosis increases Ca-albumin
Acidosis ionized Ca is increased 1.5 and less bound calcium 0.75
Direct measurement with ion specific electrodes confirms the relationship
Alkalosis (e.g. hyperventilation) can precipitate tetany
Hypocalcaemic patients with acidosis don’t develop symptoms

Answer 128

A

• Routine measurement is total Calcium; cost & convenience
• Doesn’t necessarily reflect ionised calcium;
o Total Ca affected by [albumin]
o pH influences ionised Ca
• Ionised more expensive so only use in ITU

Answer 129

A

• Not many conditions cause high albumin- mainly just dehydration, or put tornequey on too tight

Answer 130

A

can’t hold onto albumin so less bound calcium

Answer 131

A

Physiology
• Need sunlight for vit D
• Can give active vit D but very potent so don’t really want to give
• Renal patients have low calcium & vit D
• Enzyme converting inactive vit D- kidney cells regulate this so if kidneys affected low vit D low Ca

Env Factors
• Endogenous; Skin colour (lower vit D), Aging- elderly (e.g. may not get out as much)
• Exogenous; Ozone, Sunscreens & clothing, Latitude and season, Time of day (circadian rhythm), Diet & supplements

Vit D falls with AGE, BMI & BODY FAT (as vit D hydrophobic- so if lots of fatty tissue- vit D re-distributes into fatty tissue so not biologically available)

Answer 132

A

Sense how much Ca or phosphate
Low Ca= PTH secreted= act on kidneys (so more Ca reabsorption), stim enzyme so more vit D converted to active vit D, Ca from bones
PTH in zymogens- zymogens need to combine with extracell surface to release contents (need Mg to do this)- so if patient has low Ca & low Mg replace Mg first and this may sort out the low Ca
Negative feedback from Ca on parathyroid glands, positive feedback

Answer 133

A

• Hypoproteinaemia
• Vitamin D deficiency; Dietary / Malabsorption, Hepatic disease, Renal Disease (can’t hold onto Ca), End organ Vitamin D resistance
• Hypoparathyroidism;Primary, Secondary to Mg depletion
• Inadequate intake of calcium
• Pseudohypoparathyroidism (low Ca as recep is ignoring PTH); End organ PTH resistance
• Artefactual cause?
o EDTA contamination
o Venestasis will cause low adjusted calcium (total calcium is unaffected)
• Can have low Ca as post op recent blood transfusion which contains citrate (bins Ca)
• Low Ca & high PTH- Vit D deficiency
• Low Ca, high phosphate & low PTH- hypoparathyroidism

Answer 134

A

• Hyperparathyroidism
• Malignancy; Lytic lesions, Humoral eg PTHrp
• Drugs e.g. lithium affect Ca
• Vitamin D excess; 1a cholecalciferol, Sarcoidosis
• Bone disease + immobilisation
“Bones, stones, moans and groans”- bone pain, stones, abdo pain & mood dampening

Answer 135

A

• Consider Adjusted Ca - look at the albumin
• Check drug history
• Exclude excess vitamin D intake
• Check for renal failure
• Simultaneous measurement of Ca & PTH
• Consider rarer causes & more complex investigations
High calcium, PTH & low phosphate- primary hyperparathyroidism
High Ca & low PTH- malignancy

Answer 136

A

low serum ionised Ca and low plasma PTH: primary hypo PTH
increased plasma PTH and low serum ionised Ca: secondary hyper PTH (renal/nutritional)
increased plasma PTH and increased serum ionised Ca: primary hyper PTH
low plasma PTH and increased serum ionised Ca: PTH independent hypercalcemia (e.g malignancy and fit D toxicity)

Answer 137

A

Untreated mild hypercalcaemia has serious consequences
< 1.6 mmol/L is a medical emergency requiring immediate treatment

Hypercalcaemia calcium > 3.5 mmol/L is alos a medical emergency.

Answer 138

A

Major intracellular ion - small proportion in plasma – similar to Potassium
Involved in high energy reactions - e.g. those involving ATP - Na/K pumps, Hexokinase
Deficiency can cause weakness (as importnce with ATP- muscles need this) and dysfunction
Severe depletion can be fatal
Low phosphate (if undetectable)= can die of resp failure (as diaphragm is a muscle)

Answer 139

A

• Hyperparathyroidism (High PTH= causes kidneys to give out more phosphate)
• Excess losses
o renal tubular damage
o Gastro intestinal
o diabetes (diuresis)
• Poor intake; malnutrition, inadequate IVN
• ECF/ ICF redistribution - like potassium

Answer 140

A

• Often overlooked or disregarded
• Symptoms of phosphate deficiency include:
o Haemolysis, thrombocytopenia and poor granulocyte function e.g. low platelets
o Severe muscle weakness, respiratory muscle failure and rhabdomyolysis
o Confusion, irritability and coma may be due to a metabolic encephalopathy due to phosphate deficiency
o Renal dysfunction
• If confirmed treatment is essential: often necessitates changes to IV fluid regimens including TPN formulations

Answer 141

A

Commoner than generally appreciated- ‘Mg - The forgotten cation’
Up to 10% of hospital admissions
Close relationship with Ca and K disorders
Similar problem with disorders of phosphate metabolism
In Kidneys; cations move across memb, calcium & Mg closely linked

Answer 142

A

• COPD = acidotic=affects cations

Answer 143

A

Causes of Magnesium 
•	Prevalence in hospitalised patients: alone on routine estimation 6 - 11%
•	Associated with :-
o	Hypokalaemia		40%
o	Hyponatraemia 		23%
o	Hypophosataemia 	29%
o	Hypocalcaemia		25%

Answer 144

A

Renal
•	Diuretic phase of Acute Tubular Necrosis
•	Hypercalcaemic states
•	Drugs
o	Antibiotics - gentamicin / carbenicillin
o	Chemotherapy - cisplatin
o	Diuretics
o	FK506 (immunosuppressant?)
GI Tract
•	Malnutrition
•	Intravenous nutrition
•	Diarrhoea
•	Malabsorption

Answer 145

A

25% of energy maintains Na & K+ gradient across cells
• Cellular
o Reduced mitochondrial respiration (involved in ATP) & impaired phosphorylation
o Defective Na-K ATPase activity
o Impaired DNA synthesis
• Biochemical
o Hypocalcaemia
o Hypophosphataemia
o Hypokalaemia
• Endocrine; Impaired PTH release, PTH resistance in bone
• CVS; Cardiac irritability, Reduced contractility (as affects ATP)
• CNS; Hyper-reflexia,Tetany, Ataxia / Vertigo, Psychosis / Depression
• Muscle; Weakness, Muscle fibrillation, Myopathic EMG

Answer 146

A

•	Serum Mg
     o	Poor correlation with actual Mg status
     o	Of value acutely
•	Erythrocyte (RBC) Mg
     o	Poor correlation
     o	Affected by high reticulocyte count
     o	Not done very often 
•	Leucocyte Mg
     o	Good correlation &amp; predictive value
•	Muscle Mg
     o	20% body Mg
     o	Important physiologically
     o	Requires biopsy

Answer 147

A

Advocated because of high prevalence but :
• Most patients asymptomatic in hypoMg
• Many patients recover spontaneously
• Hypomagnesaemia usually manifests itself alongside obvious causative disease, eg chemotherapic side-effects.
Should always be considered with combined hypokalaemia & hypocalcaemia

Answer 148

A

Structural support
Protects vital organs (e.g. heart)
Blood cell produc (via marrow)
Storage bank for minerals (esp calcium)

Answer 149

A

• Cortical (compact) bone= hard, outer (cortex) layer (most of strength & mass);
o Multiple microscopic columns each called an osteon
o Each column- multiple layers of osteoblasts & osteocytes
o Cortical bone covered by a periosteum on outer surface & andosteum on inner surface
• Trabecular (cancellous) bone=spongy, inner layer, high surface area (metabolically active, where bone marrow & cell produc)
o Open cell porous network
o In spaces; bone marrow & haemopioetic stem cells
• Cortical majority bones- femur, trabecular majority bones- vertebrae
• Bone made of cells= bone forming & reabsorbing cells
• Extracellular= organic matrix (mainly collagen), inorganic components (hydroxyapatite- harden bone, minerals- Ca, phosphate)

Answer 150

A

Terminally differentiated products of mesenchymal stem cells.
Make osteoid (non-mineralised organic matrix (gets mineralised to make hardened bones), consists of mainly Type 1 collagen)- helps form bone
Communicate with other bone cells
Need osteoid to mineralise bone
Make hormones (e.g. osteocalcin), matrix proteins and alkaline phosphatase
Prerequisite for mineralisation
Osteoblasts that are trapped within the matrix are called osteocytes

Answer 151

A

Large & multi nucleated
Ruffled-resorption border- high surface area
Break down bone – critical for repair and maintenance of bone (this is always done)
Found in bone pits (resorption bays)
Produce enzymes such as tartrate resistant acid phosphatase (TRAP) and Cathepsin K - secreted to breakdown extracellular matrix
Help enhance blood calcium levels (can be used to maintain blood Ca levels)
PTH increases osteoclastic activity
Regulated by hormones including PTH, calcitonin and IL-6
RANK ligand (monoclonal antibody- treatment for osteoporosis) and osteoprotegrin help with osteoclastic maturation and activity

Answer 152

A

Star shaped
Trapped/buried osteoblasts in matrix
Communicate with each other via long cytoplasmic extensions
Mechanosensory properties- helps bone sense what’s going on
Involved with regulating bone matrix turnover

Answer 153

A

Extracell matrix
Protein & mineral
Mainly collagen- tensile strength
BEFORE mineralisation- called osteoid
Matrix then MINERALISED by HYDROXYAPETITE (calcium-phosphate-hydroxide salt)
Constant re-modelling
Highly vascular tissue & metabolically active
Osteoblasts constantly producing and secreting matrix and helping with mineralisation
Osteoclasts causing bone resorption

Answer 154

A

Osteoclasts- munch at them (little bone reabsorption)
Then osteoblasts= mineralisation= resting
Resting (mineralised bone) then resorption (osteoclast, ruffled border and resorption pit) the osteoid formation (osteoblasts) then mineralisation

Answer 155

A

Balance between bone formation & reabsorption changes
Peak bone mass in mid 20s
After 40- middle age- start loosing bone mass
Women- loss of oestrogen (menopause)- loose bones more
Osteoporpsosis determined by peak bone mass & rate of decline
With increasing age; decrease in bone formation & increase in bone reabsorption in bothe males and females

Answer 156

A

Gross struc- xray
Bone mass (calcium)- DEXA scan (look at bone mass/ density)- radiation shone through bone
Cellular function turnover- biochemistry
Microstruc/ cellular function- biopsy, qCT (microstruc & bone quality)

Answer 157

A

Products of active OB (products of osteoblast formation):
• Alkaline phosphatase (TAP, BAP)
• Osteocalcin (OC)
• Procollagen type I propeptides (P1NP)- marker of how much osteoblastic activity happening

Answer 158

A

Degradation products of bone collagen:
• Hydroxyproline
• Pyridinium crosslinks
• Crosslinked telopeptides of type I collagen (NTX, CTX,)- can meaure in blood
Osteoclast enzymes:
• Tartrate-resistant acid phosphatase (TRACP 5b)- released from osteoclasts
• Cathepsin K

Answer 159

A

• Measured by the laboratory in LFTs and Bone profiles
• In health approximately comes form (so if elevated look at these two);
o 50% liver
o 50% bone
• Specific isoenzymes can be measured where there is diagnostic doubt

Answer 160

A

• Phosphatase involved in mineralisation
• Released by osteoblasts
• Release stimulated by increase bone remodelling (causes of increased alkaine phosphatase);
o Childhood/ pubertal growth spurt
o Fractures
o Hyperparathyroidism (primary, secondary)
o Pagets disease of the bone

Answer 161

A

Synthesized by OSTEOBALSTS- precursor molecule of type 1 collagen
Low diurnal & intraindividual variation (doesn’t change that much during the day, can measure on diff days & get similar result)- stable marker
Serum concs NOT affected by food intake (don’t need to be fasting)
Increased with increased osteoblast activity
Decreased by reduced osteoblast activity

Answer 162

A

Cross-linking molecules released with bone RESOPTION
Increased in periods of high bone turnover (when bone breaking down get cross linking molecules); hyperthyroidism, adolescents, menopause
Have diurnal variation
DO NOT predict bone mineral density
Decrease with anti-reabsorptive therapy
Prob of CTX- varies from morning to evening (take evening), need to be fasting & certain medication affect it

Answer 163

A

• Collagen-related markers mainly based on type I collagen which is widely distributed in several tissues
• Changes in bone markers NOT disease specific, just reflect alterations in skeletal bone metabolism
• Reflects how much bone turnover but doesn’t tell you what disease so NOT diagnostic
• Some markers- signif intraindividual variability
• Uses of new bone markers;
o Evaluate bone turnover & loss
o Used for eval of treatment effect- CTX monitors response to anti-reapsorptive therapy
• Evaluation of medication compliance;
o P1NP monitors teriparatide compliance
o CTX monitors compliance/ response to anti-reabsorptive therapy

Answer 164

A

•	Measure spine &amp; hip 
•	Measures bone density 
•	Help used to determine if have osteoporosis 
•	T-scores;
o	-1 &amp; above: bone density NORMAL
o	Between -1 &amp; -2.5: OSTEOPENIA 
o	-2.5 &amp; below: OSTEOPOROSIS 
•	Gives you a T score; normal distrib 0 (mean- compared to young healthy person of same sex), if -/+1 is 1 standard deviation away from that mean

Answer 165

A

• Systemic skeletal disease characterised by low bone mass & microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture

• E.g. in spine with osteoporosis;
o Increase in biconcavity of lower thoracic bodies
o In anterior compression of mid thoracic vertebral bodes
o Wedge fracture in 2nd vertebrae
• Generalised loss of bone with propensity to fractures - spine, hip
• Several common risk factors for bone loss
• No abnormalities are seen in routine biochemical tests (may see Ca & vit D deficiency- but rare) perhaps because they are too insensitive
• Diagnosis relies on DEXA/XRay
• Increasing use of bone markers in management
• Decreased bone mass (quanity DEXA)+ deranged bone microarchitecture (quality)= failure of stuructural integrity

Answer 166

A

Fracture that occurs that shouldn’t
WHO: ‘a fracture caused by injury that would be insufficient to fracture a normal bone.’
NOS: ‘a fracture that occurs as a result of a minimal trauma, such as a fall from a standing height or less, or no identifiable trauma’
Neck of femur, hip, spine, humerus & wrist- common sites of fragility fracture

Answer 167

A

• Suspect low bone mass in any person with history of fragility fracture!
• Unexplained loss of height, kyphosis (spine curvature) or severe back pain should prompt investigation for vertebral fractures.
• FRAX calculation tool;
o Can access over the internet- for patients that you may think at risk of osteoporosis to help decide if need treatment (mainly for use by GPs)- includes risk factors & gives you a number
o E.g. 75 year old, female, 70 kgs, 160cm, previous fragility fracture, nil else = 10 year probability of major OP fracture 21% and hip fracture 6.1%.

Answer 168

A

• Any inflamm disease- risk factors for osteoporosis
• Investigations for secondary causes of osteoporosis;
o Calcium and bone profile
o U&Es (estimated GFR)- kidney function
o TFTs (thyroid function)
o FBC
o Vitamin D
o PTH
o Plasma viscosity (+/- myeloma screen)
o Coeliac screen
o In men: 9am testosterone, SHBG, LH, FSH and LFTs.
o In young amenorrhoeic women: LH, FSH, estradiol, prolactin
o Loss of height, back pain or kyphosis consider Lateral X-ray T5-L5 spine.

Answer 169

A

• Selective oestrogen recep modulator (SEMA)
• All drugs stop drug breakdown
• Only teriparatide- builds more bone
Anti resorptive treatments: SERMS (raloxifene)/Biphosphonates (oral therapy- alendronate, risedronate, ibandronate/IV therapy- zoledronate, ibandronate)/RANK-L inhibitor (Denosumab)
Anabolic treatments – parathyroid hormone analogue (teriparatide)

Answer 170

A

• E.g. Alendronate, Risedronate, Ibandronate, IV Zoledronic acid
• Mechanism of action: stops bone break down but prob as this will eventually stop bone formation, modulate signalling from osteoblasts to osteoclasts, inhibit osteioclast formation migration and osteolytic activity and promote apoptosis
• Mimic pyrophosphate structure
• Taken up by skeleton
• Ingested by osteoclasts concentrated in newly mineralising bone and under osteoclasts
• Then bisphosphate disrupts osteoclasts- apoptosis
• DIsadvs;
o Poor absorption
o Difficult to take
o Can cause oesophageal/ upper GI problems
o Flu-like side effects
o Osteonecrosis of the jaw (non-healing of jaw)
o Atypical femur fractures;
 E.g. 69-year-old woman- history of cervical & lumbar spondylosis, had bilateral thigh pain for two months before fracture. She had been on alendronate for 5 yrs. She heard a snapping sound in a) her right thigh while shopping. b) The left lateral subtrochanteric region- evidence of a stress injury

Answer 171

A

Common in several malignancies
Diff types of cancers- diff types of bone mets- 2 key types;
• Lytic
o Destruction of normal bone (osteoclast mediated)
o Breast / Lung
o Kidney/ Thyroid

• Sclerotic/osteoblastic
o Deposition of new bone
o Prostate
o Lymphoma
o Breast/lung (15-25%)
• Usual sites of spread: spine, pelvis, femur, humerus, skull
• If have high Ca= LYTIC (as as bone breaks down releases Ca into blood)

Nuclear medicine bone scan- inject radioisotope & use gamma radiation to see where it’s gone

Answer 172

A

Pain; often worse at night and gets better with movement initially, usually becomes constant
Broken bones; pathological fractures (that happen without trauma)- investigate further (commonly femur, humerus, vertebral)
Numbness, paralysis, trouble urinating; spinal cord compression from bone metastases
Loss of appetite, nausea, thirst, confusion, fatigue; symptoms of hypercalcaemia
Anaemia; as bone mets disruption of bone marrow

Answer 173

A

Mild: Polyuria, polydipsia, Mood disturbance, Anorexia, Nausea, Fatigue, Constipation

Severe: Abdo pain, Vomiting, Coma, Pancreatitis, Dehydration, Cardiac arrhythmias

Answer 174

A

Non-PTH Mediated
• Malignancy (high Ca low PTH)
• Vitamin D intoxication
• Chronic granulomatous disorders e.g. sarcoidosis
• Medications; thiazide diuretics, Lithium, Teriparatide, Theophylline toxicity
• Immobilisation
• Other endocrine conditions; hyperthyroidism, acromegaly, phaeochromocytoma, adrenal insufficiency

PTH Mediated 
•	Sporadic primary hyperparathyroidism (prob in PTH gland so will have high Ca and high PTH)
•	Familial:
o	MEN1 and 2A
o	Familial hypocalciuric hypercalcaemia
o	Familial isolated hyperparathyroidism

• HyperCA 95% of the time caused by malignancy & sporadic primary hyperparathyroidism

Answer 175

A

Secreted by chieft cells of parathyroid gland
Polypeptide contating 84 amino acids
Lots of adipose cells in parathyroid gland
Parathyroid gland has two cell types, chief cells (make PTH) and oxyphil cells (unknown function)

Answer 176

A

PTH- maintains blood Ca
As Ca levels increase, parathyroid senses this via CaSR (trasmemb GTP binding protein)- switches off/↓ PTH secretion.
In cases where this doesn’t happen hyper secretion of PTH and nonsuppressibility of PTH result.
Serum levels of parathyroid hormone & magnesium depend on each other.
Parathyroid hormone secretion physiologically controlled by serum Ca level, but Mg can exert similar effects.
Low levels of Mg stim parathyroid hormone secretion, but very low serum concentrations induce a paradoxical block (hypocalcemia in severely hypomagnesaemia patients).
The mechanism of this effect linked to activation of the alpha-subunits of heterotrimeric G-proteins- mimicks calcium sensing receptor activation so inhibits parathyroid hormone secretion.
Parathyroid hormone also in turn regulates magnesium homeostasis- modulates renal magnesium reabsorption (distal convoluted tubule- parathyroid hormone-regulated magnesium homeostasis), incraeses decomposition of bone realising Ca, and increases CA absorption from food by intestine and increases reabsorption of Ca from urine by kidneys
As previously described increased calcitriol may directly inhibit PTH secretion. Vit D =inhibition of PTH sectetion

Answer 177

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high alk phos as getting more bone turn over . Ca high, PTH inappropriatly high, Low phosphate and High ALk phos. Causes: sporadic/familial

Previously used to present with severe hypercalcaemia, and/or symptomatic renal and skeletal disease
Now presentation is much earlier in disease course and is usually asymptomatic
Majority of cases present at >45 years of age
Women twice as likely to be affected compared to men
Inappropriately elevated PTH in the presence of high calcium suggests PHPT
Usually caused by single adenoma

Answer 178

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what you’d expect but if does this excessivly over long time PTH glands loose ability to switch off & develops into tertiatey . Ca normal/low, PTH appropriatly high, phosphate high if due to CKD. Causes: CKD/VVit K deficiency

Answer 179

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Ca high, PTH inappropriatly high, Phosphate can be high or low Most common cause of tertiary- after prolonged secondary HPT usually in CKD

Answer 180

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primary Hyperparathyroidism
• Adenomas (benign)- single adenoma account for 85% of cases of primary HPT
• Glandular hyperplasia
o Approx. 6-10% of cases of primary HPT
o All 4 glands enlarged
o Can occur sporadically or part of genetic syndromes
o Medical or surgical therapy
• Ectopic adenomas
o Rarely ectopic adenomas in mediastinum
o Some parathyroid adenomas found in thymus gland
o Parathyroid cells which migrated during embryogenesis
• Parathyroid carcinoma (malignant)
o 1-2% of all cases of hyperparathyroidism
o Features of invasion on histology
o Usually aggressive disease, with significant hypercalcaemia and possibility of distant metastases

Answer 181

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Symptoms related to hypercalcaemia(as described)
Renal disease (nephrolithiasis, chronic kidney disease)
Bone disease (osteoporosis, osteitis fibrosa cystica- round tumours in hands)
Proximal muscle wasting
Bone pain
Subperiosteal bone resorption typically middle phalanges, clavicles, skull, long bones

Answer 182

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Primary HPT: Imaging. Tc 99 Sestamibi
• Right parathyroid adenoma
• Look for swollen parathyroid glands

CT SPECT (Tc-99m MIBI)
• Ectopic parathyroid tissue in mediastinum
• (1st line investigation)

Answer 183

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SURGERY
• Symptomatic hypercalcaemia
• In asymptomatic patients with primary HPT if have one of the below criteria:
o Calcium >0.25mmol/L above normal
o Renal stone disease
o Calculated creatinine clearance <60ml/min
o Age <50 yrs
o Osteoporosis at any site or history of fragility fracture
MEDICAL
• Calcimimetics (Cinacalcet)- lower Ca levels (makes PT gland think there’s more Ca then there is)
• Activates CaSR in the parathyroid gland (so leads to reduced PTH secretion)
• Use to normalise calcium in symptomatic patients, or those who are not fit for or unwilling to have surgery
• Does not seem to alter bone disease
• No data on renal outcomes or quality of life

Answer 184

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Rapid bone turnover and formation (in a chaotic manner)
Leading to abnormal bone remodelling
Mainly over 50 years old
Higher prevalence in men
Don’t know why it happens- probable genetic and environmental triggers
Fam HX in 10-15% of cases
Polyostotic or monostotic
Elevated alkaline phosphatase reflecting increased bone turnover
Bone thickening, & moisac apperance of bone
cotton wool apperance of skull

Answer 185

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Bone pain & deformity
Fractures
Arthritis- abnormal loads on knee & hp (2ndry osteoarthritis)
Cranial nerve defects if skull affected (skull getting larger)
Hearing and vision loss
Risk of osteosarcoma (ongoing pain)
Most commonly affects pelvis, femur and lower lumbar vertebrae

Answer 186

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• Investigations:
o Lab assessment
o Plain X-rays
o Nuclear medicine bone scan (locaisation- tells you which bones affected)
• What would be the best treatment?- Bisphosphonates (reduce osteoclastic activity- but as they talk to osteoblasts, also end up reducing osteoblastic activity)
• How could you monitor disease activity? – alkaline phospahtase

Answer 187

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• Lack of mineralisation of bone e.f. vit D deficiency/ resistance e.g. riskets
• Adult form - widened osteoid seams with lack of mineralisation
• Classic childhood rickets - widened epiphyses & poor skeletal growth
• Causes of osteomalacia:
o Insufficient calcium absorption from intestine (lack of dietary calcium or Vit D deficiency/resistance)

Answer 188

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• Diffuse bone pains (usually symmetrical)
• Muscle weakness
• Bone weakness (propensity to fracture increased)
• High alk phos, low Vit D (causes 2ndry hyperparathyroidism= increases PTH t get Ca), possibly low Calcium and high PTH (secondary hyperparathyroidism)
• Prolonged vit D= high alk phos (?)
• Adult population at risk
o Nursing home residents/ elderly
o Asian population (Hijab/ Burka wearing)
o Malabsorption

Answer 189

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High PTH is primary prob- low phosphate as excreting more, high pth drives osteoclastic activity= high Ca , alk phos and PTH, low phosphate

Answer 190

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Vit d deficinceny= low Ca which causes 2ndry hyperparathyroidism= high alk phos. Low phosphate and high PTH

Answer 191

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can only diagnosie via dexa scan & history. Normal Ca, phosphate, alk phos and PTH

Answer 192

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High alk phos , Normal Ca, phosphate and PTH

Answer 193

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Might get high Ca if lytic bone mets, high alk phos , low PTH, normal phoshate

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